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What is High-Risk CLL and How Is It Treated?

What is High-Risk CLL and How Is It Treated? from Patient Empowerment Network on Vimeo

What exactly is high-risk chronic lymphocytic leukemia (CLL), and how is it treated? Dr. Lyndsey Roeker discusses biomarkers that indicate high-risk CLL as well as treatment approaches that may be used for targeting specific subtypes of CLL.

Dr. Lyndsey Roeker is a hematologic oncologist at Memorial Sloan Kettering Cancer Center. Learn more about Dr. Roeker here.

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Transcript:

Katherine:                  

We have an audience question. Mike wants to know, “What does it mean to have high-risk CLL?”

Dr. Roeker:                

So, great question, and the interesting thing is that I think the answer to that question is evolving. So, deletion of 17p, deletion of 11q, and TP53 mutation have historically been markers of more aggressive disease or unfavorable CLL. In the era where we only had chemo and immunotherapy, we know that patients had less great outcomes. We know that the treatments tended to not work as well, and patients had disease that tended to come back faster, and things like that.

That’s all evolving in the era of targeted agents. We have some indication that probably patients who have more aggressive underlying disease biology, meaning disease that’s going to behave less well, kind of regardless of what we treat it with, certainly may derive less benefit, meaning that the treatment will work for less long. That being said, these treatments are still really effective for our patients who have traditionally high-risk disease. So, I think it still remains to be seen, in terms of long-term outcomes and what to expect for patients that have these traditionally high-risk characteristics.

Katherine:                  

Let’s run through a few potential results so we can understand how you might approach each patient type. If someone has deletion 17p, what is the approach?

Dr. Roeker:                 

So, there are two totally reasonable frontline treatment options.

So, BTK inhibitors, which are – the current approved ones are ibrutinib and acalabrutinib, are completely a reasonable approach in the frontline setting, meaning the first treatment that someone gets, and those are pills that you take daily. For ibrutinib, it’s once a day. For acalabrutinib, it’s twice a day, for as long as they’re working. And the idea is, with this approach, you keep on those medicines, and they keep the disease suppressed. So, that’s the first option.

The second totally reasonable option is a combination of venetoclax (Venclexta) and obinutuzumab (Gazyva). So, venetoclax is a pill and obinutuzumab is an IV medicine, and the way that this was studied was a total of one year of therapy. So, from the time you start until you’re done with all of your treatments, that’s a one-year course. And the drugs have different side effect profiles, and depending on other medical problems, patient preference about, let’s just take a pill and that’s easy, versus the combination of pill and IV medicines, either can be a completely reasonable choice.

It just depends a lot on patient and doctor preference.

Katherine:                  

What about the TP53 mutation?

Dr. Roeker:                 

So, both of those treatment options seem to work very well for TP53-mutated patients. We had that discussion about the possibility of chemoimmunotherapy for a small minority of patients, and for patients with a TP53 mutation, using chemoimmunotherapy up front is probably not the correct answer. It’s better to go with one of the targeted drug approaches.

Katherine:                  

How would you approach each patient type, if a patient is IGHV unmutated?

Dr. Roeker:                 

So, IGHV-unmutated is the same discussion. Chemoimmunotherapy is probably not going to provide a durable, meaning it’s not going to last for a long time. We’re not going to achieve that potential cure. So, for those patients, either the BTK inhibitor approach, or the venetoclax/obinutuzumab approach is completely a reasonable one to take.

Katherine:                  

And if they’re IGHV-mutated?

Dr. Roeker:                 

IGHV-mutated patients who are young and don’t have a lot of other medical problems, that’s when we add in the third option of chemoimmunotherapy. For many patients, it’s not wrong to choose either a BTK inhibitor or venetoclax/obinutuzumab, but it does add in that third potential option of chemoimmunotherapy.

Katherine:                  

Are there other markers that patients should know about?

Dr. Roeker:                 

So, TP53 mutation status, FISH, and karyotype kind of gets you most of them. Some centers do additional next-generation sequencing of other genes that have been associated with higher-risk disease, though really understanding how to interpret those results still remains somewhat unclear, and that’s still an area of research that people are doing, to really understand what those other mutations really mean for people.

What Does It Mean to Have High-Risk CLL?

What Does It Mean to Have High-Risk CLL? from Patient Empowerment Network on Vimeo.

What does high-risk chronic lymphocytic leukemia (CLL) mean exactly? Dr. Jennifer Woyach explains the meaning of high-risk CLL, factors in determining disease progression, and the impact on treatment decisions.

Dr. Jennifer Woyach is a hematologist-oncologist specializing in chronic lymphocytic leukemia (CLL) at Ohio State’s Comprehensive Cancer Center – James Cancer Hospital & Solove Research Institute. Find out more about this expert here. 

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Transcript:

Katherine:                  

We have a patient question. I have 17p deletion. Should I be worried?

Dr. Woyach:               

So, 17p deletion is usually associated with more aggressive disease biology almost always associated with that unmutated IGHV. The reason I bring that up is there are a very small subset of patients who have 17p deletion and mutated IGHV who, actually, have pretty indolent or slow growing disease.

People who don’t, which is the majority of them with 17p deletion, do have a shortened time to treatment and shortened survival with most of our current therapies. There have been a lot of advances though in the treatment of 17p deleted CLL. And may of our newer therapies can very much prolong the remission time in the lives of patients with 17p deletion.

Katherine:                  

Dr. Woyach, how do these chromosomal changes affect disease progression and prognosis?

Dr. Woyach:               

So, the markers that are associated with more aggressive disease biology usually are going to be associated with people that need treatment within the first few years after diagnosis, especially those people who have 17p deletion, 11q deletion, unmutated IGHV.

Katherine:                  

What exactly are prognostic factors? Would you define that?

Dr. Woyach:               

Sure. Prognostic factors, and I mentioned three of them, the IGHV, FISH, and the TP53 mutation, are ones that have been studied extensively and shown that the presence of this marker or some change in this marker is associated with a change in the biology of the disease or in the response to therapy.

Katherine:                  

How does the identification of these changes or mutations affect treatment options?

Dr. Woyach:               

Well, right now, we’re lucky in CLL because we have a lot of treatment options. I would say the most important changes when we’re talking about somebody with CLL that is about to start their first treatment is the decision of whether chemotherapy is ever appropriate. So, almost everybody with CLL now is treated exclusively with targeted therapies.                              

So, nonchemotherapeutic options. There are some people who are young, and in CLL terms that means under the age of 65, who have mutated IGHV and who otherwise have good genetic list disease. So, normal chromosomes of the 13q deletion, no TP53 mutation. That small subset of patients, actually, has the potential to be cured with a specific type of chemotherapy. It’s called FCR or fludarabine, cyclophosphamide, rituximab. So, for those young, healthy patients, it’s really important to know those risk factors to know if they are in that group that has that potential for cure.

The converse to that is if patients don’t fall in that group, they probably shouldn’t receive chemotherapy as their first treatment, because it’s not as effective as our other therapies.

Katherine:                  

Yeah. It makes sense.

Dr. Woyach:               

And then, even in the future with first and other treatments with novel therapies, we know that patients with 17p deletion and TP53 mutation tend to have a shorter response time. And so, what I use that for in my practice is I know that those are people that I really have to be sure that we’re following them closely, taking any signs of progression seriously, and always have a back-up plan for what we’re going to do if this treatment doesn’t work.